Drug company doublespeak: “it doesn’t work, but we know it works”

Have you ever wondered how diet drugs come into being?

The story of another new weight loss drug in the pipeline provides unsettling insights into just how flawed and flimsy the scientific evidence is from the get go.

It’s not surprising, with the incomprehensible obsession with being thin, that Fortune Magazine just reported: “the market potential for a weight loss wonder drug is enough to make any Big Pharma CEO salivate.” There’s been just one big problem: “Trouble is, safe and effective fat-fighting treatments are a Holy Grail that continues to elude pharmacological researchers.”

The reason, admitted the magazine, is that everyone is approaching the “problem” all wrong. No matter. Without going into the basic fallacies behind the “need” to get people to lose weight and reach some ideal weight, the true motivation is money. The profit potential is so enormous that Pfizer and Bristol-Myers announced this week a plan to collaborate on developing drugs for obesity and diabetes. It is hoped that “obesity” will save the day. As Fortune Magazine reports:

Both companies are in desperate need of a big-selling drug, since each has a mega-seller that will soon face generic competition. Pfizer's cholesterol pill, Lipitor - the biggest blockbuster ever, with $12.9 billion in sales last year - could lose patent protection as soon as 2010. And Bristol-Myers's blood-thinner Plavix, with $6.3 billion in 2006 revenues, is set to follow suit in 2011.

The two companies are treading in potentially lucrative, but dangerous, territory. Many a drugmaker has tried and failed to develop and market weight-loss medication. Most recently, French pharma giant Sanofi-Aventis, after creating what it considered to be an elegant solution, saw its appetite-suppressant, Acomplia, rejected by a U.S. federal advisory committee last June...

And of course, medical history is littered with a litany of would-be slimming products that have received FDA rejections and worse. Two of the category's current best-sellers, Roche's Xenical and Abbott Laboratories's Meridia, carry long lists of uncomfortable side effects. Xenical, for instance, causes some patients to lose control of their bowel movements. Famously, in 1997, the FDA took Wyeth's fenfluramine (known as fen-phen) off the market after several patients developed heart complications. The ensuing product liability litigation cost more than $15 billion.

Fortune Magazine writer, John Simons, goes on to explain why the merger is a bad idea for the companies, citing medical experts who explain that all weight loss drugs work by mechanisms “with guaranteed side effects [that] aren’t worth the benefits.” Weight loss is minimal even when people are drugged up. Our bodies are smarter, said endocrinologist, Dr. Robert Lustig. “When patients are eating less, the body ratchets energy expenditure down, because it knows it's being starved. That's why you see rapid weight-loss over the first four to six months of drug treatment, then a plateau....obesity is not a disease or a behavior. It’s a phenotype (a trait or characteristic in a subset of the population).”

Clinical trial on new drug flops

Another company has been in the news, however, pursuing its own potential blockbuster: OBE101. FDA News just reported an announcement by Bio-Light Life Sciences Investments Ltd., the parent company of Obecure, Ltd., which is a private company in Israel that holds the worldwide exclusive to “clinically develop and commercially exploit the technology as developed by [Chief Scientific Officer] Dr. Nir Barak.”

The initial results of its phase II clinical trial testing OBE101 for the treatment of obesity were released last month and had found OBE101 (Histalean™) to be ineffective.

The patients on OBE101 lost no more weight than a control group. The study authors had concluded:

There were no statistically significant differences among any of the treatment arms versus placebo.

So, they did some crunching of their data (“a post hoc segmentation analysis”) and just came back to add that “a segment of the subpopulation of women ages 50 and under showed that a certain dosage caused substantial weight loss compared with the control group.” How’s that for qualifiers? There’s more.

The Business Wire headlined this weekend with the news: “Obecure Phase II Trial Shows Positive Results for Histalean in Obese Women Under 50.”

The company press release gave these specifics: When their analysis was limited to nonhispanic women at the end of week 12, they found that “the 25 women on the 48 mg dose had lost an average of 2.61 kg of their weight, versus 23 women on placebo, who lost only 0.4 kg of their weight. This result was statistically significant with a p-value of 0.003. The effect of ethnicity on drug responsiveness in the current analysis is still inconclusive, since the number of hispanic women in each study group was very small [4 and 5 women].” The study results have not also published, so the specifics of the weight loss data through to the end of the trial and the diet program the participants followed has not been peer-reviewed.

Dr. Yaffa Beck, Obecure’s CEO, said in the company’s press release: “We are excited by the robustness of the response to the 48 mg daily dose...in this subgroup of women under 50. Combined with the drug's remarkable safety profile, this positions Histalean as a contender in the greatly unmet market for anti-obesity drugs.” With that, the company “intends to pursue additional clinical trials of the drug.”

OBE101’s past life

Is OBE101 a revolutionary new drug? This may be surprising, but it’s been around for some 40 years, under a different name.

To understand OBE101, we have to go back to when a drug called Serc, with the chemical name betahistine dihydrochloride, was first being advanced as a treatment for Meniere’s disease. This condition causes tinnitus (ringing in the ears), vertigo (dizziness) and progressive hearing loss — but commonly goes into spontaneous remission after a few years, according to the FDA. Serc had received FDA approval to be marketed in the 1960s, but for only about 5 years. Its approval was withdrawn in 1970 because of lack of evidence for any efficacy and because the claims of its effectiveness were found to have contained “deficiencies and misrepresentations.”

“For those who want the quick answer, nobody has a reasonable rationale of why betahistine should work for dizziness,” said Dr. Timothy C. Hain, M.D., professor of Neurology, Otolaryngology, and Physical Therapy/Human Movement Science, Northwestern University Medical School in Chicago, IL. The FDA’s withdrawal was upheld by a U.S. court of appeals in 1968.

At least four small double-blind trials of betahistine have been conducted since then. The FDA Center for Drug Evaluation and Research’s Pharmacy Compounding Advisory Committee again reviewed the evidence on May 7, 1999 and concluded that there was still no evidence for a therapeutic effect, and while there had been no studies of patients taking it for more than a few months, the main precautions they noted were its potential to aggravate peptic ulcers and asthma. The FDA gave it a status similar to an inert substance and put on its bulks compounding list.

Skeptic readers will enjoy learning about one of those randomized, double-blind controlled clinical trials, published in Archives of Otolaryngology-Head and Neck Surgery. It tested 119 people with vertigo using betahistine or water — “a combination of four homeopathic medicines” made by Heel, Inc. of Albuquerque, New Mexico. It reported that there was no difference in the frequency, duration or intensity of vertigo attacks during the 6-week treatment period between betahistine or homeopathy.

A 2001 Cochrane review of all of the placebo-controlled clinical trails conducted on betahistine for Meniere’s disease, published since 1966, found that none of the trials met quality standards due to poor diagnostic criteria or methods and bias. One trial with good methods found no effect compared to placebo and none of the studies showed any effect on hearing. The researchers concluded there is insufficient evidence to support claims that betahistine has any effect on Meniere’s.

But, while betahistine doesn’t have FDA approval for Meniere’s here in the U.S., it’s what is given to Meniere’s patients in the UK, prescribed by 94% of ENT surgeons there. In fact, a friend and Meniere’s sufferer in England found that it was the only prescription available to her, which is how I came to know this drug.

The makeover

So, how did Serc (betahistine) come to be repackaged as a weight loss drug and given a new name of OBE 101 (Histalean)?

According to Solvay Pharmaceuticals, which markets Serc, over 130 million Meniere’s patients worldwide have taken this drug. Did all these Meniere’s sufferers lose weight and find themselves skinny? No. There has been no outbreak of slender, dizzy people around the world. In fact, a recent comprehensive review of 35 years of worldwide drug safety data found that the most frequent side effects were sensitivity reactions (itchy rashes) and gastrointestinal complaints that were mostly nausea, vomiting and abdominal cramps. Weight loss was only mentioned once, and not the result of anything healthful. The safety review stated:

A total of three cases of neoplasm have been reported. One case concerned a male patient of unknown age who experienced weight loss, insomnia, impatience and irritability soon after the start of betahistine therapy. An undiagnosed phaeochromocytoma was suspected. The remaining two cases were assessed as being unrelated to betahistine by the reporter. Finally, four deaths have been reported during the course of postmarketing surveillance for betahistine.

So what led to the recent makeover of Serc into OBE101, and the launch of that clinical trial testing it as a weight loss drug? The answer illustrates the lengths companies will go to get approval to market a diet drug, especially from the FDA.

The only available study to suggest a link to weight was done a couple of years ago by researchers at a psychiatric hospital, also in Israel, who hypothesized that the antipsychotic drug-induced weight gain seen among schizophrenic patients might be due to histamine antagonism. So, they tested 3 male schizophrenic patients (average age of 22 years) hospitalized for acute psychotic episodes by giving betahistine along with their anti-psychotic medication (olanzapine) for 6 weeks. Incredibly, their Institutional Review Board approved this trial.

According to Obecure’s website under “Scientific Rationale: Proof of Concept,” they support this drug being studied in fat people for weight loss claiming this trial “showed that the drug prevented the weight gain normally associated with the anti-psychotic drug.”

The actual clinical trial published in Internal Clinical Psychopharmacology, however, reported something quite different: “All participants completed the 6-week trial and gained weight [average 6.8 pounds]. All demonstrated a similar pattern of weight gain over the study period...All study participants gained weight, suggesting that betahistine is ineffective in the prevention of olanzapine-induced increase in body weight.”

Weight gain, however, slowed the last weeks of the study and was less than these authors said they’d reported in other patients on olanzapine, leading the authors to say “the lack of weight gain from week 2 to the end of the study...indicates a possible attenuating effect of betahistine on olanzapine-induced weight gain. The lack of a placebo control precludes definitive conclusions.” [But this is enough to launch another clinical trial using it with olanzapine on 78 schizophrenia patients, led by Yaffa Beck, Obecure’s CEO in Israel.]

With betahistine widely used in the UK for Meniere’s, practitioners are already getting consumer inquiries about it for weight loss. This spring, ATTRACT conducted a search for evidence to support betahistine’s use in weight loss. Since 1997, ATTRACT has provided evidence-based searches, evaluations and summaries for practicing clinicians in South Wales. It concluded:

Betahistine is not licensed for this indication and ATTRACT has found no randomised controlled trials giving evidence to support its use in weight loss in the medical literature. The only reference was to a small study [the above study on those 3 hospitalized male schizophrenia patients] investigating its weight attenuating effect in patients prescribed olanzapine.

Despite the dearth of any quality clinical evidence to support betahistine/OBE101 as a safe and effective long-term weight loss drug, the press has already been proclaiming it a “super pill,” reminiscent of the “miracle pill” claims inundating us last winter for acomplia. As the Telegraph reported:

Super-pill may end misery of being fat

Scientists have stumbled upon a “super-pill" that helps people lose weight at a staggering rate – and could save the NHS millions in risky obesity surgery. The drug, Betahistine, has been safely used to treat vertigo for years, so could be fast-tracked for approval and available by 2009....

“It may take some time to find out precisely how it works. What we know for sure is that it does,” said Dr Barak. Dr Ian Campbell, of the British charity Weight Concern, says: “It's smashing news that we may soon have a new drug to treat obesity.”

Hopefully fat people and the FDA will remember the lessons of the past and not repeat history. Drug companies are hoping both will think a possible 5 pounds are worth it, whatever the costs. But when you hear glowing news of a new drug, it pays to look closely at the evidence.

© 2007 Sandy Szwarc